Methylmercury (MeHg) is a persistent environmental toxin that selectively disrupts development of the fetal brain. Human exposure to MeHg, which occurs predominantly through fish consumption, contributes to an estimated 6% of women of child-bearing age in the U.S. having blood mercury levels at or above the reference dose set by the EPA. Children born to mothers having elevated blood mercury levels show cognitive deficits. Despite the ongoing health risks posed by MeHg the discrete mechanisms that make the developing nervous system most sensitive to MeHg toxicity are not clear. As well, factors that confer resistance to MeHg intoxication are not fully understood. In this proposal we will investigate how MeHg interferes with the earliest events in neurogenesis. Our overall hypothesis is that MeHg acts specifically in the nervous system by overcoming endogenous defense mechanisms to alter activity of cell signaling pathways. Using the Drosophila (fruit fly) model, we have discovered that MeHg can activate Notch receptor signaling, a highly conserved pathway required for normal neurogenesis in flies and humans. We also find overall resistance to MeHg is achieved by upregulation of glutathione synthesis specifically in the nervous system. We will therefore investigate how these fundamental mechanisms operate to disrupt, and alternatively protect, nervous system development with three Aims. First, we will characterize three distinct cell differentiation events in embryonic neurogenesis where Notch signaling is potentially perturbed by MeHg. Second, we will identify and characterize direct interactions of MeHg with protein targets in the Notch pathway. Finally, we will identify gene products that confer MeHg resistance by artificial selection and expression profiling. These data will advance our understanding of the fundamental molecular mechanisms dictating the susceptibility of the embryonic nervous system to MeHg toxicity. [unreadable] [unreadable] [unreadable]